1. Field of the Invention
This invention relates to 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen-containing heterocycle at the 5- or 6-position bound through the nitrogen atom and a method for their preparation. These compounds exhibit anti-proliferative and anti-inflammatory activity and are useful for treating mammals with inflammatory and/or autoimmune disorders. This invention also relates to pharmaceutical compositions containing the disclosed compounds and to methods of treating inflammatory and/or autoimmune disorders employing the disclosed compounds.
2. Description of the Related Art
Certain monosaccharides and their derivatives are known to have therapeutic value in the treatment of inflammatory and autoimmune disorders. Monosaccharides, particularly the hexoses, are well known compounds. Synthesis of derivatives of these sugars can be accomplished by synthetic techniques which are known in the art.
To prepare derivatives of the monosaccharides it is common to block or protect one or more of the hydroxyl groups with acetal blocking groups such as isopropylidene or cyclohexylidene, and only leave one or two hydroxyl groups free to undergo further reaction. Various blocking groups, and methods are described in U.S. Pat. Nos. 2,715,121 and 4,056,322 and incorporated here by reference. For example, to prepare a derivative of .alpha.,D-glucose which is blocked in its furanose ring structure, the 1,2- and 5,6-hydroxyl groups can be blocked using an isopropylidene blocking group and the 3-position left open to undergo further reaction. After the reaction to derivatize the 3-position is complete, the blocking groups may be selectively removed to allow for further derivatization at other positions if desired.
Various derivatives of six carbon sugars, as well as synthetic methods, are described in U.S. Pat. Nos. Re. 30,354, Re. 30,379, Re. 32,268, 4,056,322, 4,735,934, 4,738,953, 4,996,195 and 5,010,058 copending U.S. patent application Ser. Nos. 07/658,311 and 07/757,817. The disclosures of these documents are incorporated here by reference. The therapeutic activity of monosaccharides and their derivatives is also disclosed in the above documents.
Two well known derivative of .alpha.,D-glucofuranose, having beneficial therapeutic properties is amiprilose, 1,2-O-isopropylidene 3-O-3'-(N,N'-dimethylamino-n-propyl)-.alpha.,D-glucofuranose, and its hydrochloric acid salt, amiprilose HCl (THERAFECTIN.RTM.). These compounds are known to have anti-inflammatory activity and demonstrated utility in managing the signs and symptoms of rheumatoid arthritis. More generally, these compounds have activity as immunomodulators, and therefore have a therapeutic effect on other autoimmune disorders such as psoriasis, eczema or lupus.
Deoxy derivatives of 1,2-O-isopropylidene-.alpha.,D-glucofuranose are described in U.S. Pat. No. 5,010,058. That patent describes methods of preparing deoxy derivatives of 1,2-O-isopropylidene-.alpha.,D-glucofuranose, and the use of such compounds in treating mammals with inflammatory and/or autoimmune deficiency disorders.
While some prior art monosaccharide derivatives have shown beneficial therapeutic activity, high doses of these monosaccharides, such as THERAFECTIN.RTM., are often needed to be effective and produce the desired results. Because therapy for those inflammatory and autoimmune disorders is often midterm or long-term, there is a need to develop potent, nontoxic compounds which can be orally administered to promote ease of treatment and patient compliance.
An object of the present invention, therefore, is to provide new compounds that exhibit significantly greater potency than available compounds, such as THERAFECTIN.RTM..
Other objects and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and obtained by means of the compounds, pharmaceutical compositions and methods of treatment pointed out in the appended claims.